Background: Prognosis of gastric cancer (GC) with extensive lymph node metastasis (ELM) is poor due to unresectability even without distant metastases. We conducted a phase II study to evaluate the safety and efficacy of preoperative chemotherapy with docetaxel (D), oxaliplatin (O), and S-1 (S) followed by extended gastrectomy. Methods: Eligibility criteria included histologically proven adenocarcinoma of the stomach; bulky nodal involvement around major branched arteries to the stomach (Bulky N) and/or para-aortic nodal metastases (PAN); cM0 (except para-aortic nodes); negative lavage cytology; not linitis plastica type; PS of 0 or 1; 20-75 years old. Patients received three 21-day cycles of preoperative chemotherapy of D (40 mg/m² on day 1), O (100 mg/m² on day 1), and S (80-120 mg /body from day 1 to day 14), and then underwent gastrectomy with D2 plus para-aortic nodal dissection. After surgery, patients received adjuvant chemotherapy with S-1 for 1 year. Primary endpoint was major pathological response rate, defined by the disappearance of more than two-thirds of the primary tumor. Expected and threshold value of major pathological response was set at 40% and 25%, respectively. Sample size was calculated to be 50 based on a one-sided alpha of 0.1, power of 0.8 and single-arm phase II study using a Southwest Oncology Group (SWOG) two-stage design. Results: Between Oct 2018 and Mar 2022, 47 patients were enrolled, of whom 46 were eligible for efficacy analysis. The median age was 67 years. The pathological type was differentiated in 33 patients and undifferentiated in 14. Twenty patients had only bulky N, 17 had only PAN, and 10 had both of bulky N and PAN. Clinical stage was III in 19 and IV in 28 patients. Except one patient refused chemotherapy, 46 patients (45 in three cycles and 1 in one cycle) completed preoperative DOS. Forty-four patients (94%) underwent gastrectomy, including 23 distal gastrectomy and 21 total gastrectomy, and 43 (91%) had an R0 resection. Major pathological response was confirmed in 26 of 46 patients (57% with 80% CI: 46-67), including pCR of 24%, which met the statistical significance (p<0.0001). According to the Becker’s criteria, grade 3 was 13, grade 2 was 12, grade 1b was 7, and grade 1a was 11. DOS-related grade 3/4 toxicities included neutropenia in 11 patients (24%), anorexia in 7 (16%), diarrhea in 4 (9%), and febrile neutropenia in 4 (9%). Surgery-related grade 3/4 toxicities were abdominal abscess in 5 (12%) and pancreatic fistula in 3 (7%). No treatment-related death was observed. Conclusions: Preoperative DOS followed by gastrectomy with D2 plus para-aortic nodal dissection is safe, feasible, and effective for GC with ELM. Clinical trial information: jRCTs031180028.